The incidence of pancreatic adenocarcinoma (PDA) is > 45,000 cases per year in the US and is increasing. While new chemotherapy regimens such as Abraxane and FOLFIRINOX extend overall survival, none offer the promise of long-term disease-free survival. We submit that immunotherapy can be an effective and durable therapeutic option for PDA. Here we extend both our published and unpublished clinical results and propose to develop a more advanced immunotherapy regimen for PDA by enhancing the immunologic potency of irradiated GM-CSF producing allogeneic tumor cells, known as GVAX. We hypothesize that a critical missing component of GVAX vaccines has been a potent DC activator. STINGVAX is based on a novel and highly active small molecule immune stimulator - cyclic-dinucleotides (CDNs) - which activate innate immunity through targeting the cytoplasmic, TLR-independent pathogen recognition receptor STING (Stimulator of Interferon Genes). CDNs are co-formulated with GVAX, resulting in an ideal synergy of multiple tumor associated antigens, DC recruitment and proliferation (GM-CSF), coupled with a potent DC activation stimulus (CDN). We propose that an off-the-shelf product that delivers multiple tumor-associated antigens-both characterized and unknown-directly to DCs, together with a strong Th1-skewing maturation stimulus will initiate a potent, durable and broad tumor-specific T cell response. The overall goal of this project is to conduct critical path IND-enabling preclinical pharmacology and toxicology studies that will lead to selection of a STINGVAX Pancreas clinical candidate and set the stage for informal discussions with the FDA to receive guidance on our proposed toxicology plan to support a Phase 1b clinical study. In this clinical study, we plan to assess the safety and immunogenicity of low-dose cyclophosphamide (Cy) + STINGVAX in patients with resected pancreatic cancer. On this project, we are extending our 10-year collaboration with Dr. Elizabeth Jaffee, who is at the forefront of immunotherapy treatment strategies for pancreatic cancer. Our overall hypothesis is that that co-formulation of CDNs with GVAX will provide a profound maturation stimulus to GM-CSF recruited DCs through STING-dependent activation of innate immunity, promoting initiation of Th1 CD4 and CD8 T cell immunity against a broad repertoire of tumor antigens, resulting in a more effective immunotherapy regimen for pancreatic cancer. To this end we propose four Aims, to: (1) confirm selection of our lead STINGVAX novel CDN compound that is phosphodiesterase-resistant and has non-canonical phosphate linkages; (2) evaluate single-dose local tolerance and systemic toxicity of the selected CDN compound in non-GLP pilot toxicity studies; (3) develop product characterization and release assays for STINGVAX Pancreas; and, (4) submit a pre-preIND document to FDA and request for an informal discussion. Successful completion of these Aims will set the stage for IND-enabling development activities to be proposed in a Phase 2 SBIR grant application.